Aminopropyl-2-thienyl-cycloalkenyl acetate



Patented Aug. 10, 1954 UNITED" STATES l orFIrcE Ammoritoiynzmfimm oYono ALKENYL ACETATE Frederick Leonard; Jackson-Heights; NI Y.,as-

signor to Warner-Hudnuh' Inc.,= New" Yorlr, N. Y., a corporation of Delaware 1 No -Drawing, Application 1 21; 1951, Serial No. 238,028"

lClaim; 1" v This invention relates to new"compoundsof pharmaceutical value, particularly as antispasmo'dics. 'Ihis'application is a continuation-in part of 7 my p'ri'orfiled application, Serial No. 119,197, filedOc'tobr l, 1949, now Patent No. 2,561,335.

My prior "application," Serial No. 119,197,.discloses and-claims compounds having the structural formum" in which R. dnotesa cyclohexenyl or cyclopentenyl radical, R and-R which maybe-the sameor difierent, denote alkyl' radicals contain= in'g'not over 4'ca'rbon atoms or"together' denote either a polymethylene radical containing" not over 5 carbon atoms or a polym'ethylene radical containing not*over 4 carbon atoms interrupted by an oxygen, sulfuror imino group; R denotes hydrogen, short chain alkyl radicals 'or halogens,

which may be the'sameondi'fierent; and A216- dnotes an alkylene radical containing'- notover' 6 carbon atoms. This class of compounds has been found "to be highlyeffective"antispasmodics;'

possessing the unusual property of having "high neurotropic and musculotr'opic activity;

Further investigationhasno'w establishedthat a particular limited group of compoundswithin the class set forth in my priorapplication, namelycompounds in-wh'ich -Allc in'the above formula represents a trimethylene radical; possess-surprisingly high neurotropic and muscul'otropic ac-- tivity even as comparedwith the "class set-forth in my said application; Accordingly; this appli cation is directed specifically "to compounds =h'av" ing the formula 2 V The'compou'nds of this inventionmaybe readily prepared by"reaeting acompound of thef formula l, IOHiOHzCHzHa1 RIII wherein R and R are as" above defined-"and Hill denotes i halogen, with a, compound of the termina whereinR and-R areas above definedf or"withan alkali salt thereof; this reaction may bec'ar ried out readilyiunder reflux in a? suitable soltent such" as "absolute" ethyl acetate? My compounds may also *bBl'DIGDELTd by reacting-under reflux and' a suitable solvent a compound of the fo'r mula:

N--CH2'CHELCH2OHT with an acyl halide of thesubstituted thienylacetic: acids abovedescribed. Anothersuitable method involves reacting-sa lower alkyl; e: g. methylzor" ethyl ester of I the tlii'enylacetic acids'abov'e de scribed with a dialkyla'min'opropa-nolabove set iorthmn'der conditionsaccomplishing ester in-.--"

terchange and volatilization of'the-loweralcohol; e; g. by heating-the--reactants in =a =solvent=such as: Xylene at reflux temperatures: The thienyl! acetyl chlorides from which the compounds of" my: invention may: be preparedare conveniently obtained? by treatment ofthe: corresponding alpha-substituted thienylac'etic acids: with ex---v cess thionylchlorideunder reflux ina suitable solvent such-as dry.:benzene.

The free basic esters of my 'invention; are

Water-insoluble liquids. Water-soluble saltsmay be formed by tr eating the free bases with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid or succinic acidiorwith suitable organic halides, e. g., alkyl halides such 'as methyl' chloride-'or'methyl 'bro== mide, aralkyll halides suchas -benzy-l chloride or benzyl bromide orother organic lial'i'oiies such as thienylhithyl' chloride;

Ah1ong"the"'coinpounds which ma we prepared:

aCcQIda'nce Witl'i this inventiohare the fol lowing: B-diethylaminopropyl alpha- (A -cyclohexenyl) 2 thienylacetate; 3 diethylaminopropyl alpha (A cyclopentenyl) 2 thienylacetate; 3-(1-piperidyl) -propyl alpha- (A -cyclopentenyl) 2 thienylacetate; 3 (1 piperidyl) propyl alpha (A cyclohexenyl) 2 thienylacetate; 3-dipropylaminopropyl alpha-(A oyclohexenyl)-2-thienylacetate; 3-dipropylaminopropyl alpha (A cyclopentenyl) 2 thienylacetate; 3-dibutylaminopropyl alpha-(a -cyclohenyl)-2-thienylacetate; 3-dibutylaminopropyl alpha- (A -cyclopentenyl) -2-thienylacetate; 3-di (isopropylamino) propyl alpha (A cyclohexenyl) -2-thienylacetate; 3-(1-pyrrolidyl) propyl alpha (A cyclohexenyl) 2 thienylacetate; 3 (1 pyrrolidyl) propyl alpha (A cyclopentenyl) 2 thienylacetate; 3 (4 morpholinyl) propyl alpha (A cyclohexenyl) 2 thienylacetate; 3 (4 morpholinyl) propyl alpha (A cyclopentenyl) 2 thienylacetate; 3 (4 thiomorpholinyl) propyl alpha (A cyclohexenyl) 2 thienylacetate; 3 (1 piperazinyl) propyl alpha (A cyclohexenyl 2- thienylacetate; 3-(l-piperazinyl) -propy1 alpha- (M-cyclopentenyl)-2-thienylacetate; 3-diethy1- aminopropyl alpha- (a -cyclohexenyl) -3-methyl-2-thienylacetate; 3-diethy1aminopropyl alpha- (A cyclopentenyl) 4 chloro 2 thienylacetate; 3-dimethylaminopropyl alpha-(A -cyclohexenyl)-2-thienylacetate; as well as watersoluble salts of these basic esters obtained by reacting these bases with acids and with alkyl halides in accordance with the foregoing disclosure. The preferred compound of this invention is the compound 3-diethylaminopropyl alpha-(A -cyclohexenyl) -2-thienylacetate, which has been found to have optimum antispasmodic action.

In order to demonstrate the extremely high antispasmodic activity possessed by the compounds of this invention, the followin table is given in which the preferred compound of this invention, namely B-diethylaminopropyl alpha- (A -cyclohexenyl) -2-thienylacetate, in the form of its hydrochloride (designated compound 1), is compared with the preferred compound of my prior filed application above identified, namely the compound 2 diethylaminoethyl alpha (A cyclopentenyl)-2-thienylacetate, in the form of its hydrochloride (designated compound 2). In these tests antispasmodic neurotropic activity was determined by suspending a strip of guinea pi intestine in a bath of oxygenated Lockes solution maintained at body temperature, inducing spasm in the strip by addition of an aqueous solution of acetylcholine in a concentration of one part per million and then determining the quantity of compound being tested required to prevent development of spasm induced in this manner. Musculotropic activity was determined in the same manner, except that barium chloride in a concentration of one part per five thousand was used to induce spasm. The results of these tests are indicated below.

Activity, 1cc. of bath It is evident, therefore, that the compounds of this invention possess considerably higher antispasmodic activity than the preferred compound of my prior filed application.

In addition, it has also been found that the preferred compound of this invention exhibits approximately twice the antidotal effect against bronchial spasm induced by administration of neostigmine methylsulfate as does the preferred compound of my prior filed application, as well as possessing twice the antihistaminic activity as compared with the preferred compound of said prior filed application.

The following example is illustrative of my invention:

Example A mixture of 11.1 gms. (0.05 mole) of alpha- (A -cyclohexenyl) -2 thienylacetic acid, 6.8 gms. (0.05 mole) of 3-diethylaminopropyl chloride, 7.6 gms. (0.055 mole) of anhydrous potassium carbonate, and 45 cc. of absolute ethyl acetate was refluxed for 9.75 hours. At the end of this time, the reaction mixture Was filtered and the filtrate was concentrated under vacuum. The residue was extracted with ether, the ether extracts concentrated in vacuo and the residue distilled at less than one micron pressure. 12.36 gms. of free base B. P. -134 C., 71 1.5179, were obtained.

This material was dissolved in 60 cc. of ethyl acetate and treated with the stoichiometric amount of 4.92N ethanolic HCl. Ether was then added to the solution to the appearance of a permanent turbidity, whereupon the hydrochloride crystallized on cooling. It was filtered ofi, washed first with 1 :1 ethyl acetate-ether, then with ether, and dried. Recrystallization from a solution of 3 cc. of ethanol and cc. of ethyl actate gave 10.27 gms. of the desired B-diethylaminopropyl alpha-(M-cyclohexenyl) 2-thienylactate hydrochloride, M. P. 138-139 C. Analysis gave the following results:

Calculated for C19H30C1NO2S: C=61.34, H=8.13, 0 :953. Found: 0:61.19, H='7.92, Cl=9.60.

By substituting for the alpha (A cyclohexenyl) 2 thienylacetic acid employed in the above example an equivalent amount of alpha- (A cyclopentenyl) -2 thienylacetic acid, the compound 3 diethylaminopropyl alpha- (A cyclopentenyl) 2 thienylacetate hydrochloride was obtained. Likewise, by substituting for 3-diethylaminopropyl chloride in either of the above examples an equivalent amount of 3-(1-piperidyD-propyl chloride corresponding esters of 3- (l-piperidyl) -propano1 were obtained.

Since certain changes may be made in the compounds above described without departing from the scope of my invention, it is intended that all matter contained in the above description shall be interpreted as illustrative, and not in a limiting sense.

I claim:

The compound 3 diethylaminopropyl alpha (A -cyclohexenyl) -2-thienylacetate.

References Cited in the file of this patent UNITED STATES'PATENTS Great Britain July 5, 1949 

